As is known, the "essential elements", i.e. calcium, magnesium, sodium and potassium, furthermore zinc, manganese, copper, cobalt, chromium, iron, molybdenum, vanadium and nickel are indispensable for the normal function of living organisms. The essential elements are the constituents or activators of numerous enzyme systems, they are in close correlation with the level of certain vitamins in the organism and with the function of the hormone system. The deficiency of essential elements greatly suppresses the biosynthesis of proteins, enzymes, hormones and other biologically active substances required to control the normal functions of the living organism as a whole.
It is also known that the essential element content of foodstuffs of animal and vegetable origin shows a steady decreasing tendency. This can be attributed mainly to the fact that owing to the growing intensity of plant cultivation the concentration of macro and micro elements of the soil absorbable by plants decreases gradually, and the fertilizers containing nitrogen, phosphorous, potassium and optionally calcium (as gypsum or lime), now generally applied in agriculture, are unable to supplement the essential elements (except potassium and calcium) removed from the soil. The subsequent processing purification and refinement of foodstuffs may further decrease the initially low amount of essential elements, frequently below the limit of analytical detection. Therefore, the essential elements which are unavailable from foodstuffs must be introduced into the organism from other sources.
So far, the essential elements were administered to the living organisms mainly in ionic state (as inorganic salts or sometimes as simple organic salts). These compounds were administered orally, particularly by mixing the metal salts into foodstuffs (J. Am. Dietetic Assoc. 59, 27 (1971)). However, the application of simple metal salts does not ensure good absorption and biological utilization of the essential elements, since metal salts form hardly soluble compounds (oxides, hydroxides, sulfides, phytates, etc.) in the living organism by interaction with the chymus or with some components of food or their digestion products. The metals are removed from the organism in the form of hardly soluble compounds without any appreciable biological utilization. A further disadvantage is due to the unpleasant taste of simple metal salts, which greatly restricts the amount of metal that can be mixed into foodstuffs. Moreover, the metal salts may catalyze the decomposition of easily oxidizable vitamins present in the foodstuffs.
Slightly better utilization can be ensured by administration of the essential elements to the living organism as organic chelates (e.g. complexes formed with EDTA, aspartic acid, glutamic acid, citric acid, etc.). The applicability of these compounds is, however, rather limited, since their great thermodynamical stability reduces the efficiency of metal utilization and these chelates may even remove important other trace elements from the organism. Thus e.g. the introduction of citrates in larger amounts may lead to anaemia or may aggravate the already existing anaemic state, since citric acid forms a stable complex with iron thereby removing it from the organism, and citrates also hinder the absorption of copper, an element of crucial importance in the treatment of anaemia. The overdosage of citrates or aspartates may also lead to the development of nephroliths.
Previous investigations have shown that the problem concerning the absorption and utilization of essential elements can be reduced considerably by introducing metals into the living organism in the form of appropriate biopolymer-metal chelate complexes.
The Hungarian patent specification No. 158,252 describes the preparation and biological effects of metal complexes formed with humic acid. Metal humates are readily absorbed in the living organism, but their use is strongly limited by the fact that humic acids are chemically undefined substances with widely varying composition and metal binding ability, and thus metal complexes of uniform and reproducible quality cannot be prepared from humic acids. Consequently, metal humates do not provide well defined and predictable biological effects and may also exert unpredictable and undesired side effects in the living organisms.
Of the biopolymer-iron systems specially suitable for the administration of iron, the mixed complexes chrondroitin sulfate-iron(II)-iron(III), alginic acid iron(II)-iron(III), pectin-iron(II)-iron(III) and degraded casein-iron(II)-iron(III) have been reported in the literature (published Japanese patent application No. 69 02.802; Yakugaku Zasahi 90, 120-126 (1970); Yakugaku Zasshi 90, 1480-1487 (1970); Japanese patent specification No. 13,090 (Chem. Abstr. 60, 5287f); Belgian patent specification Nos. 619,267 and 652,508). The alginic acid-iron(II)-iron(III), pectin-iron(II)-iron(III) and degraded casein-iron(II)-iron(III) systems are, like metal humates, chemically ill-defined compositions, which therefore do not ensure predictable and reproducible biological responses. Although the complex chondroitin sulfate-iron(II)-iron(III) is well defined both chemically and biologically, it has the disadvantage that the natural sources of chondroitin sulfate, required as starting substance, are very limited, and the isolation and purification of this compound is a complicated, tedious procedure.
U.S. Pat. No. 3,074,927 discloses metal complexes of reducing sugars such as iron(III) fructose and U.S. Pat. No. 2,518,135 describes metal complexes of 2-substituted glycopiranose derivatives. Although these complexes may be also used for introducing metal ions into a living organism, they are absorbed in a much smaller amount than the complexes of the invention.
Journal of Polymer Science, 10,A-I 287 to 293 (1972) discloses complexes of polygalacturonic acids formed with copper(II), cadmium(II), zinc(II) and nickel(II) ions, respectively. In these complexes the polymerization grade of the polygalacturonic acids, i.e. n is at least 150, preferably 150 to 400, according to the producer of these polygalacturonic acids, i.e. the firm ICN Pharmaceuticals, Inc., Cleveland, Ohio. However, due to the high molecular weight of the polygalacturonic acids employed in these complexes the latter are absorbed by the living organism in a much smaller amount than the complexes of the present invention. Accordingly, the complexes of the cited literature reference are not applicable for introducing essential elements into a living organism. In sharp contrast, the polygalacturonic acids of these complexes are used for removing from a living organism toxic elements such as lead and radioactive strontium. U.S. Pat. No. 3,563,978 discloses metal complexes formed with carboxymethyl cellulose, naturally occurring alginates, naturally occurring carrageenins and mixtures thereof. These complexes may be used for removing bile acids from a living organism and thus for preventing reabsorption of these acids by the small intestine. Accordingly, these complexes are not absorbed by the cells of a living organism.
It is known from French Pat. No. 860 M that hypokalaemia may be treated by administering a potassium salt of polygalacturonic acid. However, this patent fails to teach why such a salt is preferable for treating said deficiency in view of the fact that several simple salts of potassium such as the corresponding chloride or citrate are well absorbed by the living organism and are therefore usable for treating hypokalaemia.
Our aim is to produce chemically and biologically well defined biopolymer-metal complexes which ensure predictable and reproducible biological responses, release the complexed essential metals quickly and quantitatively to the oligo- and polypeptides and mucopolysaccharides of the living organism when introduced, and which can be prepared by simple methods from easily available starting substances. We have found that the compounds of the general formula (I) fully meet the above requirements. Further, we have found that the potassium or magnesium ions contained in the complexes of the invention are able to replace some of the calcium ions closing the membranes of the cells and thus make it possible for the other metal ions contained in the very same complex to come through the membrane and be absorbed by the cell.
Thus the invention relates to novel complexes of oligo- and polygalacturonic acids formed with essential metal ions and having the general formula (I), wherein n, M and z are as defined above.
The complexes of the invention may be prepared by methods known per se. Preferably one proceeds by reacting an oligo- or polygalacturonic acid of the general formula (II), ##STR3## wherein n is as defined above, with at least two salts containing M.sup.z+ ions, wherein M and z are as defined above, or with at least two complexes of metals M which have lower stability constants than the corresponding oligo- or polygalacturonic acid-metal complex (such as acetate complexes). However, potassium may also be used in the form of its hydroxide. According to our experiments this form is the most preferable. The reaction is performed in aqueous and/or polar organic media or in solid phase.
The term "metal ion" used in the specification and claims also includes the positive ions composed of metal and oxygen atoms, such as the [Mo(O)].sup.3+ ion.
We have found that the biological effects of complexes in which several types of essential metal ions are complexed by one molecule are more favorable than those of the physical mixtures of oligo- and polygalacturonic acid complexes each containing only one type of essential metal ion. By the proper selection of the ratios of the metal salt or metal complex reactants, the ratios of the metal ion types in these "polymetal complexes" or "coprecipitates" can be varied over a wide range. The coprecipitates can be applied particularly well e.g. in the treatment of anaemia, since in this instance the complete set of essential elements required for the treatment (iron, copper, cobalt, manganese, zinc, molybdenum) can be introduced into the organism with a single composition. The coprecipitates can also be used to great advantage e.g. for the treatment of diabetes, for the prophylaxis of cardiac infarction, atherosclerosis and nephrolithiasis, for the promotion of wound healing and also in geriatrics.
As mentioned above, the novel compounds of the general formula (I) can be converted into pharmaceutical compositions for oral administration, or can be mixed into foodstuffs.
For the preparation of pharmaceutical compositions, the essential metal ion complexes of decagalacturonic acid (n=10) have proved to be particularly advantageous. Pharmaceutical compositions for oral administration, e.g. tablets, capsules, pills, suspensions, etc., can be prepared by conventional procedures. If desired, the active agents of the general formula (I) can be admixed with other biologically active substances (such as vitamins) and/or conventional pharmaceutical vehicles, such as diluents, carriers, disintegration aids, adjuvants, etc. The pharmaceutical compositions may also contain more than one metal biopolymer of the general formula (I). Owing to their favorable physical characteristics, the compounds of the general formula (I) can also be tableted directly, without any auxiliary agent.
As mentioned above, the compounds of the general formula (I) can also be prepared by solid-phase reactions. Such a reaction occurs when a homogeneous mixture of the starting substances, i.e. of an oligo- or polygalacturonic acid of the general formula (II) and at least two metal salts or complexes containing M.sup.z+ ions, is tableted. Under the great pressure applied in tableting, the reaction starts in solid phase and the required metal complexes are formed in the stomach.
To increase the essential metal content of foodstuffs, the essential metal ion complexes of a polygalacturonic acid with n being equal to about 140 are preferable. These compounds can be added to foodstuffs (such as chocolates, sausages, dairy products, breads, cakes, fruit products, syrups, etc.) according to known procedures.
It should be mentioned that the terms "pharmaceutical composition" and "foodstuffs" are used in the broadest sense; they also pertain e.g. to infant formulas, dietetic products, etc.
It is also noteworthy that metal salts and/or metal complexes which contain the essential metals in higher oxidation states than specified above can also be applied for the preparation of the compounds having the general formula (I). In such cases the resulting oxidized intermediates are reduced by generally used methods to obtain the required end-products.
The following part of the specification concerns biological tests performed with compounds of the general formula (I) and the results obtained.